Dynamics of p53 DNA binding sites contributes to functional selectivity of p53-driven gene expression

Abstract

The tumor suppressor protein p53 is situated in the midst of a complex cellular network that is activated in response to cellular stress. Activated p53 functions mainly as a transcription factor, regulating the expression of numerous genes involve in various cellular pathways critical for preventing cancer, and in pathways unrelated to cancer surveillance. An unresolved question in the field is how p53 is able to parse its myriad functions in response to the severity of the stress signal and consequently to coordinate the functional outcome in a timely manner. We have previously shown that DNA torsional flexibility distinguishes between different p53 response elements (REs). Here we show across the genome that p53 target genes belonging to pathways acting early in the stress response (e.g., DNA damage response and innate immunity) have REs that are significantly more flexible than REs of genes involved in pathways that need to be more strictly regulated, or that their functional outcome occurs later in the response to stress (e.g., intrinsic apoptosis and p53 negative regulation). We validated these statistical findings by several complementary experimental approaches, in vitro and in cells, for six p53 REs belonging to pathways that operate at different times post p53 induction. Our results clearly demonstrate that the flexibility of p53 REs contributes significantly to the temporal expression of p53 target genes and thereby to life versus death decisions in the p53 system.

Electron Spin-Polarizability and Charge Dynamics in Ancient Polypeptides – Their Role in Protein Function

“…It is well accepted that the "docking" of substrates/ligands on enzymes/proteins is not an abrupt single-step event but a rather a dynamic process, influenced by the conformational dynamics of the participating biomolecules, involving multiple 'bindingunbinding' events, till the minimum-energy configuration is achieved. [39][40][41][42][43] Upon the first encounter of the DNA and the protein, electrostatic interactions induces charge-reorganization in the protein, i.e. due to the approaching negatively charge DNA electrons are repelled from the binding site in the protein (Figure 5C, panel II).…”